Activation and pulmonary toxicity of pyrrolizidine alkaloids.
Pyrrolizidine alkaloids unsaturated in the 1,2 position are hepatotoxins. Certain of them, such as monocrotaline, are also pneumotoxins, producing pulmonary arterial hypertension and right ventricular hypertrophy as a delayed response two weeks after administration. Pneumotoxicity is the result of hepatic metabolism, the lung itself being unable to bioactivate pyrrolizidine alkaloids. The changes produced in the lung following exposure to pneumotoxic pyrrolizidine alkaloids are reviewed, together with the factors and interventions which modify or influence these changes. In the main, the earliest changes are seen in vascular smooth muscle and in the interactions between the smooth muscle and the endothelium. The search to identify the pneumotoxic metabolite is reviewed. It is generally accepted that pyrroles, or dehydroalkaloids, are responsible for the toxicity of pyrrolizidines. However, the primary pyrroles are intensely reactive, hydrolyzing and polymerizing within seconds in aqueous solution. Evidence for and against the pneumotoxin being a primary pyrrole or a stabilized secondary conversion product of a primary pyrrole is discussed.
Huxtable
R J
RJ
Department of Pharmacology, College of Medicine, University of Arizona, Tucson 85724.
D000818:Animals; D006801:Humans; D008168:Lung / Q000187:drug effects*; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism / Q000633:toxicity*
D011763:Pyrrolizidine Alkaloids